In many cases naturally occurring animal models of human disorders, especially those affecting the nervous system, have not been described. We are generating transgenic mice by pronuclear microinjection of DNA into fertilized eggs and by gene targeting from the introduction of genetically modified murine embryonic stem cells into blastocyst stage mouse embryos. In cases where the gene defect has been identified, the introduction of mutations into the germ line of mice provides a unique opportunity to generate mice having appropriate phenotypes where disease pathogenesis and treatment can be studied. In addition to the generation of "null allele" or "knockout" mice, we are using other strategies, such as the LOX/CRE system, for the introduction of subtle mutations into the germline of mice. Transgenic mice with genes under the control of cell (including glial and neuronal), tissue specific, and/or inducible/repressible promoters are also being produced. The NIMH Transgenic and Targeted Mouse Resource has been established as a cooperative effort between the Veterinary Medicine Research Branch and the Clinical Neuroscience Branch, IRP, NIMH. Murine models are being produced and the developmental and tissue specific expression of genes is characterized in these transgenic mice. Our collaborative efforts, both within the NIMH and with investigators in other Institutes, to generate transgenic mouse models of human disorders are providing valuable tools that extend our understanding of human disorders and that will be useful for the evaluation of new protein/enzyme replacement, cellular transplantation, and gene transfer therapies.